(ORDO NEWS) — At the very beginning of the pandemic, doctors fought to ensure that patients breathe, and the main attention was paid to preventing damage to the lungs and cardiovascular system. But today doctors are sounding the alarm: some patients with COVID-19 have a mental disorder. The worst thing is that scientists do not understand the causes of brain infection.
The woman saw lions and monkeys in her house. She began to understand poorly what was happening, behaved aggressively towards other people, and was convinced that her husband was an impostor. The woman was about 55 years old, that is, much more than the age when psychosis usually develops. In addition, she had never had a mental disorder before. But she was sick with COVID-19. This is one of the first known cases of a person suffering from COVID-19 with a psychotic disorder.
At the very beginning of the coronavirus pandemic, doctors fought to ensure that patients breathe, and the main attention was paid to preventing damage to the lungs and cardiovascular system. Some of those hospitalized with a diagnosis of COVID-19 developed a mental disorder. These people did not understand what was happening, they were disoriented and agitated. In April, a group of Japanese scientists published the first report that a patient with COVID-19 developed a tumor and inflammation of the brain tissue. Another report described a patient with a breakdown of myelin (a mixture of lipid and protein substances that protect nerve fibers), which is usually irreversibly damaged in the case of neurodegenerative diseases such as multiple sclerosis.
“The neurological symptoms are getting worse and worse,” says neurologist Alysson Muotri of the University of California, San Diego.
The list today includes stroke, cerebral hemorrhage, and memory loss. This is unheard of, but the scale of the COVID-19 pandemic suggests that thousands and even tens of thousands of people could have such symptoms, and some of them could have lifelong health problems as a result.
However, scientists cannot find answers to key questions, including fundamental ones, for example, how many people have this condition, and who is at risk. There is also a more important question to which they want an answer: why these symptoms occur.
The virus can enter the brain and infect it, but it is unclear to what extent SARS-CoV-2 does this. Neurological symptoms can appear as a result of overstimulating the immune system. Understanding this is extremely important because these two scenarios require very different treatment regimens. “This is why disease mechanisms are so important,” says Benedict Michael, a neurologist at the University of Liverpool.
As the pandemic gained momentum, Michael and his colleagues were among a large group of scientists who began to collect information on the neurological complications associated with COVID-19.
In their work published in June, they analyzed the course of the disease in 125 British people who fell ill with COVID-19 and received neurological and psychiatric complications. In 62% of them, the blood supply to the brain was damaged as a result of a stroke or hemorrhage, and in 31% there were changes in the mental state, such as confusion and prolonged unconsciousness. This is sometimes accompanied by encephalitis when the brain tissue becomes inflamed. 10 people with an altered mental state developed a mental disorder.
But not all people with neurological symptoms were seriously ill and were in intensive care. “We saw a group of relatively young people without the usual risk factors for stroke and patients with severe mental changes that cannot be explained,” says Michael.
Similar work was published in July. This study compiled data from 43 patients with neurological complications from COVID-19. Some patterns are emerging, says neurologist Michael Zandi of University College London, who is the lead author of the July study. The most common neurological sequelae are stroke and encephalitis. The second can turn into an extremely severe form called acute disseminated encephalomyelitis when inflammation of the brain and spinal cord begins, and nerve cells lose their myelin sheath. This causes symptoms like multiple sclerosis. Some of these severe patients had only mild respiratory symptoms. “In their case, the underlying disease was brain damage,” says Zandi.
There are also more rare complications, including damage to peripheral nerves, which is typical of Guillain-Barré syndrome. Zandi calls it “all sorts of things,” highlighting things like anxiety disorder and post-traumatic stress disorder. Similar symptoms have been reported during outbreaks of SARS and Middle East respiratory syndrome (MERS), which were also caused by coronaviruses. But in those cases, there were much fewer cases, and therefore there is little information on them.
How many people?
Doctors don’t know how common these neurological effects are. In July, another study was conducted on this topic, whose participants estimated the prevalence of such effects, using data on other coronaviruses. At least 0.04% of people with SARS and 0.2% of people with Middle East respiratory syndrome had symptoms of central nervous system damage. Given the fact that there are 28.2 million confirmed cases of COVID-19 in the world today, we can say that from 10 to 50 thousand people have faced neurological complications.
But when determining the number of people with neurological complications, a serious problem arises. The fact is that in clinical trials, the main focus is usually on those patients with COVID-19 who have been hospitalized, and above all, those who are in intensive care units. The prevalence of neurological symptoms in this group can exceed 50%, says neurologist Fernanda De Felice of the Federal University of Rio de Janeiro. However, there is much less information available on patients with mild or asymptomatic disease.
This lack of data makes it difficult for scientists to understand why some people develop neurological symptoms and others do not. It is equally unclear how long these complications last. Covid-19 may have other health consequences that last for months, and some coronaviruses leave symptoms for years to come.
Infection or inflammation?
But the most pressing question for many neurologists is why the brain suffers at all. The patterns of disease are fairly consistent, but the underlying mechanisms are still unclear, De Felice says.
The answer to this question will help doctors choose the right course of treatment. “If this is a direct viral infection that affects the central nervous system, then we should treat these patients with redelivering or another antiviral drug,” says Michael. “But if this virus is not in the central nervous system, then we need to use anti-inflammatory drugs.”
Misunderstanding can be harmful. “It makes no sense to give antiviral drugs to those whose virus has disappeared, and it is very risky to give anti-inflammatories to those who have the virus in their brains,” says Michael.
There are clear indications that SARS-CoV-2 can infect nerve cells. The Muotri team specializes in growing organelles, as they call miniature pieces of brain tissue. They are obtained due to the fact that human pluripotent stem cells are modified, turning into neurons.
In a preliminary analysis published in May, the team showed that SARS-CoV-2 can infect neurons in these organelles, killing some of them and preventing connections between them from forming. The work of immunologist Akiko Iwasaki and her colleagues at Yale University School of Medicine in New Haven, Connecticut appears to support this. They used in their research human organelles, the brain of mice, and the results of anatomical autopsies. Their results were published on September 8th. But questions remain about how the virus enters the human brain.
Loss of smell is a common symptom, and therefore neurologists have suggested that the pathway may be the olfactory nerve. “Everyone thought there was such a possibility,” says Michael. However, research data refutes this.
A team of researchers led by pathologist Mary Fowkes of the Icahn School of Medicine at New York’s Mount Sinai Center published a paper in late May describing the autopsy results of 67 people who died from COVID-19. “We saw the virus in the brain itself,” Fawkes says. His presence was detected using electron microscopes. However, the concentration of the virus was low, and it was not possible to detect it always and everywhere. Further, if the virus penetrated through the olfactory nerve, then first of all, according to the logic of things, the areas of the brain associated with it would be affected. “We just don’t see the virus in the olfactory bulb,” Fawkes says. Most likely, she notes, the infection in the brain is minor, and it is concentrated mainly around the blood vessels.
Michael agrees that finding the virus in the brain is difficult compared to other organs. Polymerase chain reaction (PCR) analyzes often does not detect them there, despite their high sensitivity. Several studies have been conducted, but participants have not been able to find virus particles in the cerebrospinal fluid that surrounds the brain and spinal cord. One of the reasons may be that the ACE2 receptor (a protein on a human cell through which the virus enters) is not very pronounced in brain cells.
“It looks like a viral infection of the central nervous system is incredibly rare,” says Michael. This means that many of the problems that doctors observe in clinics can be the result of the body’s immune system fighting the virus.
However, in some cases, the picture may be different, and therefore, researchers will have to identify biomarkers that can reliably distinguish between viral brain infection and immune activity. This means that new clinical and physiological studies and autopsies will be needed.
De Felice and his colleagues plan to monitor patients who have recovered from intensive care and create a biological sample bank, including cerebrospinal fluid. Zandi says similar research has begun at University College London. Undoubtedly, over time, scientists will figure out all these samples.
While the questions they seek answers arise in almost every outbreak, COVID-19 poses new challenges and simultaneously creates new opportunities, Michael says. “We have not had a pandemic of this magnitude since 1918,” he explains.
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